Imethylene blue nesifo sikaParkinson: ubungqina bophando lwaphambi kovavanyo ebantwini nolwezonyango

Khangela imethylene blue nesifo sikaParkinson, uya kufumana amabango aqinisekileyo asekelwe kubungqina obubuthathaka. Isifundo esinye kwiimpuku apha, uvavanyo kwiiseli phaya, ngasinye sinikezelwa ngokungathi unyango sele lukufuphi. Inyaniso imxinwa ngakumbi yaye inomdla ngakumbi. Kukho uphando lokwenene olujoliswe kwisifo sikaParkinson, lugxile ekukhuseleni imitokondriya, kodwa lukude kakhulu ekunikeni ubungqina ebantwini. Eli nqaku lidwelisa olo phando, isifundo ngesifundo, ukuze ubone ngokuchanekileyo into ekhoyo nengasekhoyo.

Isizathu sokuba abaphandi bahlale bebuyela kule khompawundi sicacile. Iineuron zedopamine ezikwisubstantia nigra zifuna amandla amaninzi kakhulu, yaye ukusilela kwecomplex I kunye noxinzelelo lweoksideshini ziphakathi kwezinto eziphambili kwiimodeli ezininzi zesifo sikaParkinson. Imethylene blue yidayi ejikeleza phakathi kweemeko zokunciphisa nezokwenza ioksideshini, enokwamkela iielektroni kwiNADH ize izidlulisele kwicytochrome c, ngaloo ndlela idlule ngokuyinxenye kwi-complex I eyonakeleyo ngoxa ithomalalisa uxinzelelo lweoksideshini. Indlela esebenza ngayo le nkqubo yokudlulisa iielektroni kwimitokondriya ngumsonto odibanisa lonke uvavanyo lwesifo sikaParkinson olungezantsi. Kufanelekile ukuqonda indlela le nkqubo esebenza ngayo ngaphakathi kwiiseli nakwizinto eziphilayo ziphelele phambi kokugweba nasiphi na isiphumo esinye. Abafundi abangaqhelananga nale khompawundi mabale kuqala indlela imethylene blue esebenza ngayo kwinqanaba leeseli. Gcina loo mfanekiso engqondweni. Uchaza kokubini isithembiso sayo neendawo apho ingcaciso ingasasebenzi khona.

Isifundo sokukhusela istriata

Uvavanyo olucace kakhulu olunxulumene nesifo sikaParkinson lwafaka irotenone, ityhefu yecomplex I, ngokuthe ngqo kwistriata sempuku, kunye okanye ngaphandle kwemethylene blue efakwe kuloo ndawo. Irotenone iyodwa yabangela imimandla emikhulu yomonakalo ababhali abayifanisa nemivumbo ebangelwa kukuphazamiseka kwemetabolism. Idayi efakwe kunye nayo yanciphisa umthamo womonakalo malunga nesiqingatha, yagcina ukusebenza kwecytochrome oxidase, yaza yathintela ukunyuka koxinzelelo lweoksideshini kwiindawo ezijikeleze umonakalo. Yagcina nokusebenza kwemetabolism kwiindawo ezidityanisiweyo ezilawula intshukumo, kuquka isubstantia nigra nepedunculopontine nucleus, yagcina ukunxibelelana okusebenzayo kwiisekethe zebasal ganglia, yaza yanciphisa ngokuyinxenye ukungalingani komsebenzi wokuva nowentshukumo phakathi kwamacala omzimba.

Zimbini izinto ezibalulekileyo ezinciphisa indlela ezinokutolikwa ngayo ezi ziphumo. Okokuqala, idayi yanikwa kunye netyhefu, kungekhona emva kokuba umonakalo sele ukho, ngoko oku kukuthintela kwimeko efana novavanyo lwaselabhoratri kunokuba kukunyanga isifo. Okwesibini, imethylene blue ayizange ibuyisele ukusebenza kwecomplex I kwimitokondriya eyahluliweyo. Ukhuseleko lwavela kwinkxaso echasene neoksideshini nakwinkxaso yemetabolism ejikeleze indawo eyonakeleyo, kungekhona ekulungiseni icomplex eyonakeleyo ngokwayo. Lo mahluko ubonakala kulo lonke uncwadi lophando.

Izifundo zokukhusela idopamine

Imodeli yeempuku echaphazela umzimba wonke yasondela ngakumbi kwiinguqulelo zesifo sikaParkinson zokwenene. Irotenone efakwe ngempompo encinci yanciphisa idopamine kwistriata yaza yabulala iineuron zedopamine kwisubstantia nigra, ngoxa imethylene blue enikwe kunye nayo ngedosi ephantsi yabuyisela amanqanaba edopamine phantse ngokupheleleyo yaza yanciphisa kakhulu ukulahleka kweeneuron, ukuthintelwa kwecomplex I-III, iintlobo zeoksijini ezisebenza ngokukhawuleza, kunye nokusilela kwiimvavanyo zerotarod, ukuhamba necatalepsy (PMID 21454572). Isifundo sesibini serotenone kwiimpuku, esasebenzisa ukufakwa kwedosi phantsi kwesikhumba, safumanisa ukuncipha okuhambelana nedosi kwiperoksideshini yeelipidi, igliosis, iTNF-alpha necaspase-3, apho eyona dosi iphezulu yagcina ngcono ukubonakala kwetyrosine hydroxylase xa ifakwa ibala. Kwinqanaba lemitokondriya, imethylene blue kuxinano lwenanomolar yanyusa ihydrogen peroxide njengomqondiso wehormesis ngaphandle kokonakalisa iDNA yemitokondriya, yaye ukunikezelwa kwayo kwangaphambili kwakhusela imitokondriya esezantsi kumbindi wobuchopho kumonakalo wemtDNA obangelwa yirotenone.

Uphando lweMPTP kwiimpuku ezincinci lubonisa indlela efanayo, kodwa kukho isilumkiso esibaluleke ngakumbi. Ukunikezelwa kwangaphambili kwe20 mg/kg/day kwagcina iineuron zenigrostriatal kunye nedopamine kwistriata, kukho ubungqina bokubandakanyeka kwenkqubo yokuthumela imiqondiso yeBDNF (PMID 29882218). Okukholisa ngakumbi kukuba isifundo seMPTP/probenecid yexesha elide saqalisa ukunika imethylene blue ngomlomo kuphela emva kokuba ukusilela kokunuka sele kubonakele, kodwa saphucula ukunuka, ukulungelelaniswa kweentshukumo nokusinda kweeneuron zedopamine (PMID 29684508). Okubaluleke kakhulu kukuba elo qela lenza uvavanyo lolawulo olucelwa ngabathandabuzayo, laza labonisa ukuba idosi ephantsi ayizange iyinciphise iMPP+ kwistriata, eyimveliso enetyhefu yemetabolism; oku kukhupha eyona ngcaciso ilula yesiphumo esiphambukisayo sovavanyo. Uphando kwiiseli zeeneuron zedopamine ezinyangwe ngeMPP longeza iinkcukacha zendlela yokusebenza: ukubuyiselwa kokusebenza kwecomplex I neATP kunye nokuthunyelwa kwemiqondiso echasene neoksideshini yeAKT-Nrf2 (PMID 34352280), kunye nokukhutshelwa kolwazi lofuzo lweparkin okuqhutywa yiNRF2 nokubuyiselwa kokwenziwa kwemitokondriya kwimodeli yoxinzelelo olungapheliyo.

Impuku ye6-OHDA, imodeli eqhelekileyo yomonakalo okwicala elinye, inika esona siphumo sincinci. Imethylene blue enikwa ngomlomo yonke imihla, eyaqalwa emva kotyando, yagcina kancinane iineuron zedopamine kwisubstantia nigra yaza yaphucula iinkalo zokunikela ingqalelo, kodwa ayizange ibuyisele umsebenzi wentshukumo okanye wemilenze yangaphambili (PMID 28694175). Isiphumo esincinci sinolwazi oluluncedo. Ikhompawundi ebonakala ibuyisela yonke into kuyo yonke imodeli idla ngokungabuyiseli nto kwaphela. Apha, ipateni yoncedo iyahluka ngendlela ibhayoloji yokwenene eyahluka ngayo.

Icandelo lealpha-synuclein

Ngokwahlukileyo kuphando lweetyhefu, inkqubo yemethylthioninium ekwimo encitshisiweyo yavavanya ukuba ikhompawundi iphazamisa na ukudibana kwealpha-synuclein ngokwayo ibe ziimfumba. Kwiiseli ezivelisa ialpha-synuclein yomntu, imo encitshisiweyo yasusa iimfumba zangaphakathi ezikwinqanaba lokuqala nezinemicu, ngeEC50 ekufutshane ne1 micromolar, yaye ukunikezelwa ngomlomo kangangeeveki ezintandathu kwanciphisa utshintsho olubangelwa sisifo kwiindawo ezininzi zobuchopho ngoxa kuphucula iipateni zentshukumo ezingaqhelekanga kwiimpuku ezincinci eziguqulwe imizila yemfuza (PMID 29375308). Isifundo sokulandelela kumgca wesibini weempuku eziguqulwe imizila yemfuza safumanisa ukuba ialpha-synuclein ekwiisynapse ibuyele kumanqanaba afana naweempuku zohlobo lwendalo, kwaza kwalungiswa ukungaqheleki kwezamkeli zeglutamate, nangona kungazange kubekho ziphumo ziqinisekisayo kwindlela yokuziphatha (PMID 35709886).

Qaphela utshintsho lwekhompawundi. Ezi zifundo zasebenzisa iLMTM/HMTM, ityuwa ezinzisiweyo ekwimo encitshisiweyo eyaphuhliselwa inkqubo yeAlzheimer, kungekhona ichloride ekwimo eoksidayiziweyo ethengiswa njengedayi. Ukusebenza kwenye imo akuthethi ngokuzenzekelayo ukusebenza kwenye; lo mahluko uchazwa ngokubanzi ziingxelo zeemvavanyo zeAlzheimer.

Izizathu ezithathu zokufunda isiphumo ngasinye kabini

Okokuqala, phantse zonke iidosi zinikwa kunye netyhefu okanye ngaphambi kwayo. Idayi ikhona ngaphambi kwetyhefu okanye ngaxeshanye nayo. Oku kuvavanya ukuba inkxaso yemitokondriya inokuthintela na umonakalo, nto leyo eluphando olusemthethweni, kodwa ayimeli isigulana esiqalisa isongezelelo emva kweminyaka yokulahleka kweeneuron esele kwenzekile.

Okwesibini, imethylene blue ithintela kanye ienzayim eyenza iMPTP isebenze. IMPTP, eyisandulela setyhefu, ayinabungozi de iMAO-B iyiguqule ibe yiMPP+. Imethylene blue ithintela olo guquko kuxinano lwenanomolar, ngoko isiphumo sokhuseleko kwisifundo seMPTP sinokuthetha ukuba ityhefu ayizange yenziwe isebenze, kunokuba kuthethe ukuba iineuron zasindiswa. Isifundo sexesha elide esingasentla siyakwazi ukumelana nale nkcaso ngenxa yovavanyo lwaso lolawulo lweMPP+. Izifundo ezingenalo olo lawulo azikwazi.

Okwesithathu, umonakalo obangelwa ziityhefu awusiso isifo sikaParkinson. Irotenone, iMPTP ne6-OHDA zivelisa ngokuthembekileyo ukulahleka kwedopamine noxinzelelo lweoksideshini, kodwa azivelisi ukuqhubela phambili okwenzeka kumashumi eminyaka, ukusasazeka komonakalo wesynuclein, okanye ukwakheka ngokutsha kweesekethe zesifo somntu. Ukukhuselwa kwezilwanyana sisizathu sokwenza iimvavanyo, kungekhona umboniso wangaphambili weziphumo zazo.

Ubungqina ebantwini: abukabikho

Ukusukela ngo2026, akukho vavanyo olupapashiweyo olwabiwa ngokungacwangciswanga, yaye akukho vavanyo longenelelo oluqhubekayo nolubhalisiweyo lwemethylene blue, iLMTM okanye iHMTM lwesifo sikaParkinson. Uhlalutyo lwakutshanje lonyango ludwelise ukuba azikho iimvavanyo zikaParkinson ezipapashiweyo yaye azikho eziqhubekayo. Iinkqubo ezibhalisiweyo zeLMTM/HMTM zijolise kwisifo seAlzheimer nakuhlobo lwesifo sengqondo esixhalabisayo sefrontotemporal esigxile ekuziphatheni, yaye iziphumo zazo azinakudluliselwa kwisifo sikaParkinson. Nabani na othengisa imethylene blue ngeenjongo zokunceda iimpawu zikaParkinson namhlanje wenza uqikelelo olusuka kwiimpuku nakwiiseli. Olo qikelelo lusilele kuninzi lweekhompawundi ezazicingelwa ukuba zinokukhusela iineuron nezazibonakala zithembisa ngakumbi kunale.

Imiba yokhuseleko ejoliswe kwizigulana zikaParkinson

Eli candelo alisosilumkiso ngokubanzi. Lijongene nokusebenzisana namayeza athathwa ngokwenene zizigulana zikaParkinson. Imethylene blue engaguqulwanga sisithinteli esinamandla nesibuyisekayo seMAO-A, esithintela neMAO-B kuxinano oluphezulu. Irasagiline, iselegiline nesafinamide zizithinteli zeMAO-B ezineelebhile ezikwalelayo okanye ezilumkisa ngokudityaniswa kwazo nezinye izithinteli zeMAO, kuba ukuthintelwa okudibeneyo kubeka umngcipheko wobutyhefu beserotonin nokunyuka okuyingozi koxinzelelo lwegazi. Ukongeza imethylene blue kwinkqubo enjalo yamayeza kukusebenzisana okubalulekileyo kwezonyango, yaye akukho datha yesifo sikaParkinson eqinisekisa ukuba iimo ezincitshisiweyo zeLMTM/HMTM ziyakuphepha oko.

Ukusebenzisana namayeza okudakumba asebenza kwiserotonin kubhaliwe ebantwini. Kuhlalutyo olucwangcisiweyo lweemeko zokudideka emva kokufakwa kwemethylene blue ngomthambo, ama25 kwama26 eemeko enzeka kwizigulana ezazithatha iyeza lokudakumba elisebenza kwiserotonin, yaye iimveliso zemethylene blue ezithathwa ngomlomo nazo zibangele iimeko ezixeliweyo zeserotonin syndrome. Ukudakumba kuqhelekile kwisifo sikaParkinson yaye kudla ngokunyangwa ngeSSRIs okanye ngeSNRIs, ngoko oku kungqubana kunokwenzeka ngakumbi apha kunakuninzi lwamaqela abantu. Iinkcukacha ezipheleleyo zokhuseleko nokusebenzisana namayeza kunye nomfanekiso obanzi wophando lwezonyango zibeka le mingcipheko kumxholo wayo. Nabani na ocinga ngokusebenzisa imethylene blue kunye namayeza kaParkinson okanye amayeza okudakumba ufuna ukonganyelwa yingcali yezonyango ngaphambi kokwenza naluphi na uvavanyo, kungekhona emva kokuvela kweempawu.

Isishwankathelo singangena kuluhlu olunye. Iimodeli zeetyhefu nezesynuclein zibonisa ukhuseleko olungaguquguqukiyo lwemitokondriya nedopamine, kunye neempendulo zokwenene ezihambelana nedosi; imithombo emithathu ekhankanyiweyo yeziphumo eziphambukisayo zovavanyo inciphisa indlela esinokutolikwa ngayo isiphumo ngasinye seMPTP nesokunikezelwa kunye netyhefu; yaye ubungqina bokusebenza ebantwini bumi kwiimvavanyo eziyiqanda. Leyo yinkqubo yophando efanele ukulandelwa, hayi unyango olufanele ukuthengwa.